Superantigens

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Superantigens are molecules which can directly activate T cells and can bind to various immune cells.

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SUPERANTIGENS:

SUPERANTIGENS BY Dr. Lavanya Gudapuri

PowerPoint Presentation:

kalilalali@hotmail.com 2 Superantigens Philippa Marrack and John Kappler discovered an interesting type of pathogen-related antigen — which they named superantigen.

Introduction :

Introduction Designation for group of proteins that use a common, extremely efficient mechanism of T lymphocyte stimulation. Activate large number of T cells irrespective of their antigenic specificities Bind to MHC Class II on APC & to parts of T cell receptors (CD4, CD8)

PowerPoint Presentation:

Thus mimics recognition of specific antigen Crosslink MHC II with TCR V β chain Interaction is independent of peptide sequence Not processed and presented by MHC

Differences:

Differences Antigens Specific activation of T cells Bind to particular epitope on the TCR Activate 0.01 – 0.001% of T cells Superantigens Non Specific activation of T cells Bind to V β chain of TCR Activate 20 – 60% of T cells

Contd.:

Contd. Produced by bacteria, viruses, protozoa. Undermine the specificity of the immune system Most effective of the T cell stimulators Have high potency active at 10 -9 mol/lit.

Consequences :

Consequences 1) Shock : mediated by massive release of cytokines 2) Immunosupression : due to uncoordinated activation of immune system 3) Autoimmunity : due to bypass of auto reactive T & B cells

Staphylococcal Superantigens:

Staphylococcal Superantigens Staphylococcal Enterotoxins A-E, Staphylococcal Enterotoxins G-P, Toxic Shock Syndrome Toxin 1,

Streptococcal Superantigens:

Streptococcal Superantigens Streptococcus pyogenes Exotoxin A,B,C,E, & G1 Streptococcal Mitogenic Exotoxin Z Most potent of Superantigens

Superantigens produced by microorganisms:

Superantigens produced by microorganisms Pathogen Protein Pseudomonas aeruginosa Exotoxin A Yersinina pseudotuberculosis Yersinia Pseudotuberculosis Mitogen ( YPM) Mycoplasma arthritidis Mycoplasma Arthritidis Superantigen (MAS) MMTV Orf (Open Reading Frame) HERV Orf (Open Reading Frame)

Doubtful Superantigens:

Doubtful Superantigens Pathogen Superantigen Staphylococcus aureus Exfoliative toxins A & B Streptococcus pyogenes M protein, Mitogenic Factor Clostridium perfringens Enterotoxin Mycobacterium tuberculosis Escherichia coli Toxoplasma gondii

Types :

Types 2 types : Exogenous & Endogenous Exogenous : produced by bacteria and released on infection. Endogenous : identified in mice thymic cells Suspected of playing integral role in viral infection.

Genetic Basis:

Genetic Basis Most genes encoding are in close proximity Undergo much variation Normal super antigens have 8 – 10 alleles Exception Streptococcal Mitogen Z, has about 20 alleles.

Contd.:

Contd. Also present on mobile segments of bacterial genomes like plasmids or pathogenic islands Operon known as “enterotoxin gene cluster” found in most SAg producing bacteria.

Structure:

Structure Crystal structures : ellipsoidal proteins with characteristic two domain protein folding Oligosaccharide/oligonucleotide fold, a long α helix diagonally spanning to the centre of the molecule. Have sites for binding MHC II & TCRs

Binding :

Binding MHC Class II : Preference for HLA – DQ Binding by α chain Puts in position to bind to TCR Staphylococcal SAgs capable of cross-linking MHC molecules. Induces production of cytokines & co-stimulatory molecules

PowerPoint Presentation:

T Cell Receptor: Variable region on β chain of T cell receptor. SAg capable of binding to multiple sites Interaction varies with each type of Sag

PowerPoint Presentation:

Based on binding to TCR Classified into 5 classes. Class Members I TSST-1 II SEB-like III SEA-like IV SPEC-like V SPEH-like

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Group I : V β at CDR2 framework Group II : V β at specific amino-acid side chains Group III : Conformation dependent binding Group IV : engage all 3 CDR loops of V β chain Group V : not determined

PowerPoint Presentation:

Binding of SAg wedges MHC & TCR. Displaces antigenic peptide away from TCR and thus circumvents normal activation Stronger the affinity to TCR, stronger is the response of SAg

T Cell Signaling:

T Cell Signaling SAg link across MHC & TCR induces signaling pathway Proliferation of cell & production of cytokines Protein Kinase C & Protein Tyrosine Kinase pathways activated. Results in massive production of pro-inflammatory cytokines Alternate pathways : Calcium/Calcineurin ; RAS/MAPKinase

Direct Effects:

Direct Effects 1) T Helper cells : massive release of IL 1, IL 2, IL 6, TNF α , Macrophage Inflammatory protein 1 (MIP 1 α , MIP 1 β ), Macrophage chemoattractant protein (MCP) 1. Result in fever, rash, multi organ failure, coma & death Deletion of activated T cells result in non responsive memory cells formed by IL 10.

PowerPoint Presentation:

INF α : due to prolonged SAg exposure, induces auto immunity. E.g. Kawasaki disease MHC cross-linking with TCR suppresses Haematopoisis, & up-regulates apoptosis Activation of T cells result in CD40 ligand responsible for isotope switching in B cells

Indirect Effects:

Indirect Effects Mitogenic activity Monocytic cell Activation & release of large amounts of TNF α leading to tissue necrosis Emesis : by SAg produced by bacteria causing food poisoning. Induce gastrointestinal toxicity and cause emesis

SAg & Endotoxins:

SAg & Endotoxins Augments activity of endotoxins Schlievert demonstrated that when administered in conjunction, effects of both SAg & endotoxin are magnified 50,000 times. Due to reduced immune system functioning

PowerPoint Presentation:

Interaction of T cell receptor (TCR) and MHC loaded with antigenic peptide during the normal T cell activation (A) and during superantigenic activation by staphylococcal enterotoxins (B). The latter can be inhibited by polyclonal antibodies such as anti-SEB hyperimmune serum as shown in (C).

Endogenous Superantigens:

Endogenous Superantigens Mouse Mammary Tumor Virus Provirus infected cells express vSAg on the surface of B cells Infected B cells stimulate T cells with appropriate V β region Activated T cells further stimulate B cells to proliferate along with viral genome in it

PowerPoint Presentation:

This viral genome persists till mammary gland is matured Then the provirus inserts in mammary epithelial cell genome and activates endogenous cellular oncogenes. Transmitted to newborn mice through milk

PowerPoint Presentation:

Mice already harboring MMTV provirus, delete T cells whose V β region is bound to vSAg Thus the mouse would be immune to infection in future. MMTV whose vSAgs are thus deleted are infectious, but they are not capable of reaching mammary gland for further transmission.

Endogenous SAgs in Humans:

Endogenous SAgs in Humans Not yet found in humans. Ascribed role in infection with EBV, Rabies, HIV Recent evidence: Provirus coded HERV-K18 Inducible by INF α Proposed pathway of environmental factors causing diseases in genetically susceptible individuals

Diseases associated with superantigen production:

Diseases associated with superantigen production Toxic Shock Syndrome Scarlet fever Kawasaki Disease Eczema Psoriasis Rheumatoid arthritis

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